Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Our plain-English summary of Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma, by A. Bononi, K. Goto, G. Ak, et al (Proceedings of the National Academy of Sciences of the United States of America, 2020).

The study

• Authors: A. Bononi, K. Goto, G. Ak, Y. Yoshikawa, M. Emi, S. Pastorino, L. Carparelli, A. Ferro, M. Nasu, J.H. Kim, J.S. Suarez, R. Xu, M. Tanji, Y. Takinishi, M. Minaai, F. Novelli, I. Pagano, G. Gaudino, H.I. Pass, J. Groden, J.J. Grzymski, M. Metintas, M. Akarsu, B. Morrow, R. Hassan, H. Yang, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2020;117(52):33466-33473
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

Copyright © 2020 the Author(s). Published by PNAS.

In plain English

This study combined genetic testing of mesothelioma patients with laboratory and mouse experiments. The authors sequenced inherited (germline) DNA from 155 mesothelioma patients: 33 familial and 122 sporadic cases treated at the US National Cancer Institute. In a Turkish family, a mother and son with pleural mesothelioma carried a predicted harmful BLM mutation. In a US family, a woman with mesothelioma and her brother, who also developed mesothelioma, carried a different one. Five sporadic patients carried BLM mutations the authors classified as pathogenic; three of the five self-reported asbestos exposure. Overall, 7 of 155 unrelated patients carried pathogenic germline BLM mutations in one gene copy. The authors reported this as significantly more than the 1 in 900 expected in the general population (P = 6.7E-10). Reducing BLM increased chromosome damage in crocidolite-exposed mouse cells and improved survival of exposed human mesothelial cells. Mice with one faulty Blm copy injected with crocidolite developed mesothelioma more often than normal littermates (21 of 25 versus 13 of 23). The authors proposed that these mutations increase susceptibility to asbestos carcinogenesis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic sequencing study of mesothelioma patients and families, with cell-culture experiments and an animal experiment in mice
• Who was studied: 155 mesothelioma patients: 33 familial (10 patients in 4 Turkish families; 29 patients with a family history of mesothelioma, 28 from the US and 1 from Turkey) and 122 sporadic pleural and peritoneal mesothelioma patients treated at the US National Cancer Institute. Also 29,553 individuals from the Healthy Nevada Project, and Blm+/- mice (25) compared with normal (WT) littermates (23), followed for 16 months after the last asbestos injection.
• Exposure: Inherited (germline) BLM gene mutations in patients, some of whom reported asbestos exposure. In the laboratory, cells were exposed to crocidolite asbestos. Mice were injected in the abdomen (intraperitoneally) with a total of 5 mg crocidolite: ten 0.5 mg injections, given twice a week for 5 weeks in the inflammation experiment and once a week for 10 weeks in the long-term experiment.
• Main results:
  • In one Turkish family, a mother and son, both with pleural mesothelioma, carried the BLM mutation c.569_570delAG
  • In the Turkish family, the same mutation was found in a currently healthy 39-year-old brother; the healthy father and sister had normal (wild-type) BLM
  • Among 29 patients with a family history of mesothelioma, 1 (a 57-year-old US woman) carried BLM mutation c.968A>G. Her brother, who carried the same mutation, developed mesothelioma at age 67.
  • In both families with a pedigree, relatives carrying the same BLM mutation as the first identified patient had developed mesothelioma
  • 5 of 122 sporadic National Cancer Institute patients carried pathogenic BLM mutations: 2 with pleural and 3 with peritoneal mesothelioma
  • Of these five sporadic patients with BLM mutations, three self-reported a history of asbestos exposure
  • Overall, 7 of 155 unrelated mesothelioma patients carried germline pathogenic heterozygous BLM mutations. The authors reported this as significantly higher than the expected general-population frequency of 1 in 900 (P = 6.7E-10).
  • 2 of the 7 apparently unrelated mutation carriers had the same mutation, c.968A>G, which the authors reported as statistically significant (P = 0.0017) given an allele frequency of 0.00039
  • In the Healthy Nevada Project, 80 of 29,553 individuals carried loss-of-function BLM variants. Of the 74 with matched electronic health records, 10 had cancer diagnoses.
  • Mouse mesothelial cells exposed to crocidolite had more micronuclei (a sign of chromosome breakage) in Blm+/- cells (10.68 plus or minus 7.24) than in WT cells (3.43 plus or minus 1.77%), P less than 0.001
  • Human mesothelial cells with BLM silenced survived crocidolite exposure better than control cells (44.1 plus or minus 10.9% versus 24.2 plus or minus 5.3% viable), P less than 0.01
  • In a cell transformation test with crocidolite and TNF-alpha, there was no significant difference in the number of transformed foci between BLM-silenced cells (63.5 plus or minus 7.0) and control cells (69.3 plus or minus 11.4), P = 0.425
  • Silencing BLM in macrophage-like cells increased their release of TNF-alpha
  • Blm+/- mice injected with crocidolite had significantly higher levels of TNF-alpha, IL-1 beta, IL-3, IL-10 and IL-12(p70) in peritoneal fluid than WT littermates, and more M1 macrophages
  • Mesothelioma developed in 21 of 25 Blm+/- mice (84.0%) compared with 13 of 23 WT littermates (56.5%), P = 0.0453
  • Median mesothelioma-free survival was 334 days in Blm+/- mice versus 362 days in WT littermates, P = 0.0264
• The authors' conclusion: The authors proposed that germline BLM heterozygous mutations increase susceptibility to asbestos carcinogenesis, increasing the risk of developing mesothelioma
• Limitations the authors state:
  • Tumor biopsies from the US families were not available
  • DNA of the deceased parents in the US family was not available for testing
  • Some of the 80 Healthy Nevada Project carriers may be relatives; this information was not available
  • The frequency of BLM mutations across all cancers is not yet known

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis, Crocidolite, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Germline Mutation, Mesothelial Cells, Macrophage, Carcinogenesis.

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• Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations — M. Carbone, H.I. Pass, et al. (2022)
• Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma — A. Napolitano, L. Pellegrini, et al. (2016)
• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations — S. Pastorino, Y. Yoshikawa, et al. (2018)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)

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